Is TRPM8 p.Ala640Pro (c.1918G>C) pathogenic?

TRPM8 p.Ala640Pro (c.1918G>C) is classified Uncertain significance in TRPM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1.

How common is TRPM8 p.Ala640Pro (c.1918G>C) in the general population?

TRPM8 p.Ala640Pro (c.1918G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRPM8 p.Ala640Pro (c.1918G>C)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

TRPM8 p.Ala640Pro

c.1918G>C · rs2469854680 · VCV3183431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic · top 1% in TRPM8
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -15.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 44 kb · p 0.85 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRPM8
Protein: p.Ala640Pro
Coding: c.1918G>C
MANE Select: NM_024080
dbSNP: rs2469854680
Type: single nucleotide variant
Location: chr2:233966648 (GRCh38)
Gene constraint: LOEUF 0.945 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.42 · 6 PDB
Residue 640: an α-helix

Full TRPM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPM8 p.Arg247Thr Benign ★★ same type
TRPM8 p.Asn821Ser Benign ★★ same type
TRPM8 p.Glu545= Benign ★★ same type
TRPM8 p.Leu226= Benign ★★ same type
TRPM8 p.Met462Thr Benign ★★ ⚠ same type
TRPM8 p.Pro916= Benign ★★ same type
TRPM8 p.Ala1071Pro Uncertain significance ★ ⚠ same type
TRPM8 p.Ala1071Val Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/trpm8-p-ala640pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown